The effect of streptozotocin and a high-fat diet on BOP-induced tumors in the pancreas and in the submandibular gland of hamsters bearing transplants of homologous islets

Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro

“…They formed anaplastic invasive tumors, similar to those induced by BOP in islets growing in the SMG of hamsters (10,11) and to PC-1.0 cells, derived from a primary BOP-induced pancreatic cancer (31). The anaplastic and invasive nature of the KL5B tumor could be related to massive overproduction of TGF-α, which was shown to be overexpressed in metastasizing ILA cells (32) derived from tumors induced in the SMG of hamsters after homologous islet transplantation (9-11) and in human pancreatic cancer cells (33)(34)(35).…”

“…In the hamster model, which mimics human disease in many clinical and biological aspects, we have demonstrated that pancreatic adenocarcinoma originates not only from ducts and ductules (2-6), but also from islets (7)(8)(9)(10)(11). In fact, the first morphological change that occurs during pancreatic carcinogenesis is the appearance of ductular structures within islets (intra-insular ductules) or around the islets (peri-insular ductules) (2,4,6,8).…”

“…The intra-insular ductules proliferate forming either benign patterns consistent with human pancreatic microcystic adenomas or becoming increasingly hyperplastic, dysplastic and atypical and culminating in the formation of malignant glands that destroy the islets and invade the surrounding tissues, even when they are of microscopic size (4)(5)(6)8). The following observations support the role of islets in pancreatic ductal carcinomas: (i) streptozotocin pretreatment, which causes destruction of β-cells, inhibits the pancreatic carcinogenicity of N-nitrosobis(2-oxopropyl)amine (BOP) at low doses or prevents it at high doses (12)(13)(14); (ii) genetically diabetic hamsters with atrophic islets are resistant to the pancreatic carcinogenic effects of BOP, whereas the pancreas of a non-diabetic strain with intact islets is susceptible (15); (iii) induction of nesidioblastosis enhances pancreatic carcinogenesis (16); and (iv) transplantation of homologous islets into the submandibular gland (SMG) of recipient hamsters and subsequent BOP treatment induces invasive and metastasizing ductal-type adenocarcinomas, histological and immunohistochemical analyses of which point to the derivation of tumors from within islets (9)(10)(11).…”

Pancreatic cancer microenvironment

“…57,60 In this regard, the general importance of beta cells for cancer manifestation has been demonstrated by previous reports showing that specific destruction of this cell population by streptozotocin treatment protects hamsters from experimental pancreatic cancer development. 61 Apart from the loss of growth-promoting insulin action, the beneficial effects of beta cell depletion on cancer development might also point toward a role of the endocrine cell compartment as a/the cellular precursor pool for PDAC, although this remains speculative in the setting of human PDAC (see ''Precursor lesions'').…”

Are islet cells the gatekeepers of the pancreas?

“…Only after the hamster model was established, did it become possible to examine the stepwise pancreatic tumor development at all stages of carcinogenicity. When treated with the pancreatic carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP), Syrian golden hamsters develop pancreatic adenocarcinomas, which mimic the human disease morphologically, biologically and molecular biologically [19,[27][28][29][30][31][32][33][34][35][36]. The research on this animal model also directed the attention of pancreatologists to the, thus far, neglected islets.…”